The objective of this research is to better understand the role of the ciliary central pair in childhood health and disease. Defects in ciliary beating result in a variety of abnormalities, including sinusitis (sinus infection), neonatal respiratory distress, otitis media (ear infection), male infertility, female infertility, hydrocephalus (water on the brain), and situs inversus (a reversal of left-right asymmetry). Respiratory and ear infections are common in young children and are usually treated with antibiotics, while neonatal respiratory distress is one of the leading causes of death in newborns. Hydrocephalus is extremely debilitating and potentially fatal if untreated by surgical shunting, and infertility is a major societal concern that impacts families on a regular basis. While all of these disorders are multifactorial, any or all of them can be associated with primary ciliary dyskinesia (PCD), a syndrome that affects approximately one in 16,000 newborn children worldwide and is caused only by defects in motile cilia function. Consequently, this research is of interest to basic scientists, clinicians, and the general public. Although several genes have been implicated in PCD in human patients and mouse models, little is known about how ciliary function is regulated. Mice homozygous for the nm1054 mutation lack primary ciliary dyskinesia protein 1 (Pcdpl), and mice homozygous for the big giant head (bgh) mutation lack sperm flagellar protein 2 (Spef2). Both mutants have PCD, and both proteins localize to the ciliary central pair, enabling further studies focusing on the role of the central pair in ciliary disease. Based on the phenotypes of these mutants, we hypothesize that the central pair regulates the dynein motor force required for proper ciliary beating. We also hypothesize that central pair proteins have a testis-specific function that underlies a distinct pathway required for spermatogenesis. The primary goals of this proposal are to dissect the molecular pathways by which Pcdpl and Spef2 regulate both sperm differentiation and ciliary motility, which will further elucidate the mechanisms perturbed in PCD and its associated disorders.